tbuckley/cabot-search huggingface dataset:
Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor
Authors: Jia‐Jia Zhang, Chang‐Geng Song, Ji‐Min Dai, Ling Li, Xiang‐Min Yang, Zhi‐Nan Chen
Journal: MedComm (2022)

Abstract Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.
Truth Telling
Authors: Reena George
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
P1427: MONITORING CAR-T CELL IN B-CELL LYMPHOMA PATIENTS THROUGH SINGLE CHAIN VARIABLE FRAGMENT BY DIGITAL PCR
Authors: I. De La Iglesia San Sebastián, D. Carbonell, A. Pérez Corral, M. Bastos, R. Bailén, M. Silvia, M. Chicano, P. Muñíz, G. Oarbeascoa, J. Anguita, M. Kwon, J. L. Díez-Martín, I. Buño, C. Martínez-Laperche
Journal: HemaSphere (2022)

Background: CD19-targeted chimeric antigen receptor (CAR)-T cell is a treatment for B-cell lymphoma patients. CAR-T cell monitoring is important to ensure a correct follow-up, being multiparametric flow cytometry (MFC) the actual gold standard technique. However, other molecular techniques such as digital PCR (dPCR) could add complementary information that could be valuable to predict CAR-T response. Both available commercial antiCD19 CAR-T cell therapies, Tisagenlecleucel (tisa-cel) (Kymriah®) and Axicabtagen Ciloleucel (axi-cel) (Yescarta®) share the single variable fragment domain (FMC63), which makes possible the measurement by dPCR. Aims: To evaluate the usefulness of digital PCR for monitoring CAR-T cell levels in comparison to multiparametric flow cytometer. Methods: Forty-five patients diagnosed with diffuse large B-cell lymphoma (36), transformed-follicular lymphoma (7) and mediastinal primary large B-cell lymphoma (2), treated consecutively with anti-CD19 CAR-T cell therapy between June 2019 and May 2021 were included in this study. One hundred and forty-two peripheral blood (PB) samples were collected at days +7, +14, +30, +90 (40, 39, 40 and 23 samples, respectively) after infusion. DNA was purified using the Maxwell® RSC Whole Blood DNA Kit (Promega, USA). dPCR assays were performed on the QIAcuity One platform (QIAgen, Germany). MFC analysis was performed on a DxFLEX cytometer (Beckman Coulter), using CD19 (20-291) protein-FITC (ACRO Biosystems). To assess the sensitivity of molecular methodologies, serial dilutions from 100% to 0.001% of CAR-T were analyzed by dPCR. Correlation of CAR-T cell detection between MFC and dPCR was calculated using Pearson’s test. Results: A high correlation between dPCR and MFC was found (r = 0.90), demonstrating the usefulness of dPCR to quantify absolute number of CAR copies (Figure 1A and 1B). dPCR improved the detection capacity of MFC, detecting CAR-T in 15 samples that were negative by MFC because of low CAR-T cell presence in PB (Figure 1C), as MFC measures CAR-T events in total PB the low content of CAR-T could reduce MFC sensitivity. Median number of CAR-T cells detected by dPCR was greater than that quantified by MFC in each days of the follow-up (Figure 1D). Different CAR-T cell products (Yescarta and Kymriah) differ in its expansion rates, therefore tisa-cel expand before axi-cel (near day 7th and day 14th, respectively) (Figure 1C). Image:Summary/Conclusion:FMC63 quantification through dPCR was effective for CAR-T measurement, even improving MFC sensitivity, especially when CAR-T counting in PB is low in late monitoring days. dPCR monitoring could complement data given by MFC and being a very sensible gold standard technique in late monitoring as its sensitivity is very superior to MFC in those follow-up days.
Gender bias in sports medicine: an international assessment of sports medicine physicians’ perceptions of their interactions with athletes, coaches, athletic trainers and other physicians
Authors: Yuka Tsukahara, Melissa Novak, Seira Takei, Irfan M Asif, Fumihiro Yamasawa, Suguru Torii, Takao Akama, Hideo Matsumoto, Carly Day
Journal: British Journal of Sports Medicine (2022)

To evaluate the difference between female and male sports medicine physicians regarding disrespectful attitudes and sexual harassment perceived from athletes, coaches, physicians, athletic trainers (ATs) and organisations/administrations.anonymous survey was distributed to sports medicine physicians practicing in 51 countries. χ2 analysis was used to detect differences between female and male sports medicine physicians and logistic regression analysis was used to determine the independent variables that affect disrespectful attitudes and sexual harassment from sports participants.1193 sports medicine physicians (31.9% female) participated from 51 countries. The survey revealed that female physicians, compared with male physicians, perceive significantly more disrespect or have their judgement questioned more by the following categories: male and female athletes, male and female coaches, female physicians with more years of experience, male physicians (regardless of years of experience), male and female ATs and organisation/administrations (all p<0.05). The only category where the frequency of disrespect was perceived equally by male and female physicians was during their interactions with female physicians who have the same or lesser years of experience. Female sports medicine physicians noted more sexual harassment than male physicians during interactions with male athletes, coaches, ATs and physicians (all p<0.001). In the logistic regression, gender was a related factor for perceiving disrespect, especially from male coaches (OR=2.01) and physicians with more years of experience (OR=2.18).Female sports medicine physicians around the world experience disrespectful attitudes, questioning of their judgement and are sexually harassed significantly more often than male counterparts.
Bumps in the Road
Authors: John W. Ostrominski, Tiffany Y. Hsu, Anna C. Garza-Mayers, Anand Vaidya, Derrick J. Todd
Journal: New England Journal of Medicine (2022)

An 18-year-old man presented to the emergency department with painful red bumps on both legs and his left ankle. He reported that the lesions had appeared 2 weeks before presentation and had begun to interfere with walking. . . .
P1238: EFFICACY ANALYSIS OF PEGASPARGASE, GEMCITABINE, OXALIPLATIN, DEXAMETHASONE COMBINED WITH TISLELIZUMAB IN FIRST-LINE TREATMENT OF PLASMA EBV-DNA POSITIVE EXTRANODAL NK/T CELL LYMPHOMA
Authors: X. Yuan, Z. Zhu, R. Ma, L. Wang, H. Li, L. Jiang, K. Sun
Journal: HemaSphere (2022)

Background: Positive circulating EBV-DNA is associated with a very poor outcome in Natural killer/T cell lymphoma (NKTCL). Efforts to further improve treatment of plasma EBV positive NKTCL are urgently needed. Aims: To investigate the clinical efficacy, plasma EBV-DNA load and safety of P-GEMOXD combined with anti-programmed death 1 (anti-PD-1) antibody Tislelizumab in first-line treatment of plasma EBV-DNA positive NKTCL. Methods: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18–70 years with newly diagnosed NKTCL who were EBV-DNA positive in plasma in Henan People’s Hospital. Patients received four courses of P-GEMOXD plus Tislelizumab treatment (pegaspargase 2500U/m2 [day3], gemcitabine 800mg/m2 [day1 and 8]; oxaliplatin100 mg/m2[day1], dexamethasone 20mg/d [day1-4]; Tislelizumab 200mg /d [day9] every 21days). Thirteen patients were enrolled from January 2018 to August 2021 December, the median follow-up was 26 (12-46) months. The short-term and long-term clinical efficacy, load of EBV-DNA and adverse reactions were observed. Results: Among the 13 patients, there were 9 males and 4 females, the median age was 54 years old (range 25-64). After 4 courses of treatment, 10 patients (76.9%) had complete response, 3 patients (23.1%) had partial response, and the objective response rate (ORR) was 100%. The 2-year progress-free survival (PFS) rate was 76.9%, and the 2-year overall survival (OS) rate was 85.7%. Among them, there were 6 patients with advanced stage (III and IV), 4 patients (66.7%) had complete response, 2 patients (33.3%) had partial response, 5 patients (83.3%) plasma EBV-DNA converted negative; the 2-year progression-free survival (PFS) rate was 66.7%, and the 2-year overall survival (OS) rate was 66.7%. Treatment-related AEs of any grade occurred in 84.6% (11/13) of all patients. The main adverse reactions were albumin reduction (8/13), fibrinogen reduction (9/13), autoimmune diseases (3 cases：1 case of hypopituitarism， 1 case of Hashimoto’s thyroiditis, and 1 case spondylitis). Summary/Conclusion: P-GEMOXD plus Tislelizumab can significantly improve the prognosis of patients with NKTCL, improve the rate of plasma EBV-DNA negative conversion, and the adverse reactions can be well tolerated.
P1417: PROPHYLACTIC NAC PROMOTED HEMATOPOIETIC RECONSTITUTION BY IMPROVING ENDOTHELIAL CELLS AFTER HSCT: A PHASE 3, OPEN-LABEL RANDOMIZED TRIAL
Authors: Y. Wang, Y. Kong, H.-Y. Zhao, Y.-Y. Zhang, Y.-Z. Wang, L.-P. Xu, X.-H. Zhang, K.-Y. Liu, X.-J. Huang
Journal: HemaSphere (2022)

Background: Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggest that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Aims: Investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT. Methods: A phase 3, open-label randomized trial was performed. Based on the percentage of CD34+VEGFR2(CD309)+ endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14d before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk(EC≥0.1%) or high-risk(EC<0.1%); patients at high risk were randomly assigned(2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60d post-HSCT. Secondary endpoints included cumulative incidences of leukemia relapse(CIR), GvHD, nonrelapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), and adverse events. This clinical trial was registered at www.clinicaltrials.gov as # NCT03967665. Results: Between April 18, 2019, and June 24, 2021, 120 patients with BM EC <0.1% were randomly assigned for NAC (Group A, N=80) or nonprophylaxis (Group B, N=40), and 105 patients with EC≥0.1% (Group C) were also analyzed. The +60d incidence of PGF and PT was 7.5% (95% CI, 1.7% to 13.3%) and 22.5% (95% CI, 9.1% to 35.9%) in Group A and Group B (hazards ratio, 0.317; 95% CI, 0.113 to 0.890; P = .021) and 11.4% (95% CI, 5.2% to 17.6%) in Group C (hazards ratio, 0.643; 95% CI, 0.242 to 1.715; P = .373) (Figure A). Consistently, NAC prophylaxis gradually improved BM ECs and CD34+ cells in Group A, whereas reduced their ROS levels post-HSCT. With a median follow-up of 347 days (range, 60-844days) post-HSCT, the 1-year probabilities relapse, NRM, OS (Figure B), and LFS (Figure C) were similar among the three groups. Within 60days post-HSCT, the most common grade 3 to 5 adverse events for the NAC and control groups were infections (19/80 [24%] vs. 10/40 [25%]) and gastrointestinal adverse events (16/80 [20%] vs. 7/40 [18%]). There were no treatment-related deaths. Image:Summary/Conclusion: N-acetyl-L-cysteine prophylaxis can prevent the occurrence of poor hematopoietic function and is well tolerated in haploidentical HSCT. It may offer a potential pathogenesis-oriented therapeutic approach for patients with poor hematopoietic function.
P569: GILTERITINIB AND QUIZARTINIB IN RELAPSED/REFRACTORY (R/R) ACUTE MYELOBLASTIC LEUKEMIA (AML) WITH FLT3 MUTATIONS: A REAL-LIFE EFFECTIVENESS AND SAFETY STUDY
Authors: D. Quintela, M. Morgades, A. Serrano, M. Cervera, A. Balerdi, M. Díaz-Beyá, M. Arnan, A. Garrido, R. Coll, M. Tormo, J. López-Marin, B. Merchan, S. Garcia, M. Casado, A. Sampol, J. Esteve, D. Martínez-Cuadrón, J. Sierra, M. Á. Sanz, J. M. Ribera, P. Montesinos, S. Vives
Journal: HemaSphere (2022)

Background: Patients with R/R AML have poor prognosis. FLT3 mutations worsened the prognosis but offer a targeted therapy. FLT3 inhibitors have demonstrated efficacy as monotherapy in FLT3-positive R/R AML. Aims: The objective of the present study was to analyze the efficacy and safety of Gilteritinib and Quizartinib in R/R FLT3-mutated AML in real-life context. Methods: Between December 2016 and April 2021, 22 patients were treated with Gilteritinib and 5 patients with Quizartinib in 13 centers of the Spanish PETHEMA and CETLAM groups. Results: The median age was 62 years (range 25; 81) and 56% were women. Most patients presented ITD FLT3 (80%), 56% were refractory and 44% were relapsed (CR1 duration ≥6 months in 60%). The 1st line therapy was intensive chemotherapy (78%, 38% with midostaurin) or HMA (22%). A total of 13/27 patients (48%) had previously received a FLT3 inhibitor (midostaurin=6, sorafenib=2, quizartinib=2, midostaurin + crenolanib vs placebo=2 and midostaurin + quizartinib=1). Seventy percent of the patients received >1 line of treatment prior to Gilteritinib/Quizartinib (the most frequent was FLAG-IDA). Compared with diagnosis, patients in R/R had poorer functional status (ECOG<2 88% vs. 73%) but lower leukocyte counts, LDH level and FLT3 ITD ratio (21.5 x109/L vs 4.7x109/L, 563 U/L vs 330 U/L and 0.60 vs 0.42, respectively). Three patients displayed clonal evolution in R/R with acquisition of cytogenetic alterations in patients with altered karyotype at diagnosis and appearance of alterations in patients with normal karyotype. The ORR was 63% (21% CR, 21% CRi and 21% PR) and the median OS was 5.8 (95%CI, 3.8; 7.9) months. Time to achieve better response was 1.8 months (range 0.9;4.1). Eight patients received the FLT3 inhibitor as a bridge to SCT, and six of them were finally transplanted. Gilteritinib dose was 120mg/day, increasing to 200mg/d in 41% of patients (due to lack of response after 28 days). Toxicity was observed in 69% of patients (g3/4 in 30%). Febrile neutropenia was the most frequent toxicity (35%) followed by hepatotoxicity (28%) and QTc prolongation (16%). One patient died of toxicity attributed to Gilteritinib (febrile neutropenia). Summary/Conclusion: Treatment with Gilteritinib and Quizartinib as monotherapy is an effective and tolerable option for patients with R/R FLT3-mutated AML in real-life, with similar response rates and toxicity to those reported in Phase 3 trials, despite the fact that the study population from our series was more heterogeneous.
The Future of Transplantation
Authors: Jeffrey L. Platt, Marilia Cascalho
Journal: New England Journal of Medicine (2022)

Since 1902, animals have been studied and occasionally used as sources of organs for transplantation, usually when human organs were unavailable. Clinical organ xenotransplantation invariably failed, whereas clinical organ allotransplantation rose to become a primary treatment for failure of the heart, kidneys, liver, and lungs. Still, a shortage of human organs has limited organ transplantation and motivates ongoing efforts to advance xenotransplantation into clinical practice. Griffith and colleagues1 now report in the Journal the transplantation of a heart from a pig into a patient who had severe cardiac failure. The pig was genetically engineered to disrupt certain genes, including those . . .
The Impending Crisis of Access to Safe Abortion Care in the US
Authors: Daniel Grossman, Jamila Perritt, Deborah Grady
Journal: JAMA Internal Medicine (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
P1134: OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA POST-CBTK INHIBITOR THERAPY IN THE UNITED STATES AND JAPAN: A STUDY OF TWO REAL-WORLD DATABASES
Authors: S. Rai, L. Hess, Y. Chen, P. Abada, H. Konig, R. Walgren, Y. Tanizawa, Z. Cai, M. Tajimi
Journal: HemaSphere (2022)

Background: Patients with mantle cell lymphoma (MCL) have limited treatment options following covalent Bruton's tyrosine kinase inhibitor (cBTKi) therapy, with no standard regimens defined. Aims: The aim of this study was to investigate real-world treatment patterns and the outcomes for patients with MCL following cBTKi treatment utilizing two separate datasets—one from the US and one from Japan. Methods: De-identified patient-level electronic medical record data from two real-world databases (ConcertAI in the US and Medical Data Vision in Japan) were utilized for this study. Eligible patients were ≥18 years old and were diagnosed with MCL between January 2011 and October 2020 in the US or between December 2010 and July 2020 in Japan. Data were available through 2020 to allow a minimum of 1 year of follow-up for all patients. Patients were required to have completed treatment with at least one cBTKi during the first through third lines of therapy. Time-to-event analyses utilized the Kaplan-Meier method. Results: 946 US patients (median age 72 years, male 75.1%) and 196 Japanese patients (median age 78 years, male 73.5%) met the eligibility criteria. 352 (37.2%) patients in the US and 103 (52.6%) in Japan received subsequent post-cBTKi therapy. The remaining 387 (40.9%) patients in the US and 93 (47.5%) patients in Japan did not receive further treatment. In the US, immediate post-cBTKi regimens included rituximab (with or without other chemotherapy agents, n=152, 43.2%) or additional cBTKi-based 146 (41.5%) or B-cell lymphoma 2 inhibitor–based (n=30, 8.5%) therapy. In Japan, immediate post-cBTKi regimens were nearly exclusively chemotherapy based (n=92, 89.3%), and only 11 (10.7%) patients were retreated with cBTKi-containing regimens. Median time from the end of cBTKi therapy to discontinuation of the immediate post-cBTKi therapy or death was 3.9 months (95% confidence interval [CI]: 3.3-4.6) in the US and 2.4 months (n=196, 95% CI: 1.7-3.0) in Japan. Among those who received post-cBTKi therapy, the duration of therapy was 2.6 months (95% CI: 2.1-3.3) in the US and 1.8 months (n=103, 95% CI: 1.1-2.3) in Japan. Median overall survival (OS) from discontinuation of cBTKi therapy was 10.3 months (95% CI: 8.0-13.0 in US patients and 7.1 months (n=196, 95% CI: 4.6-12.7) in Japanese patients. Summary/Conclusion: Patients with MCL previously treated with cBTKi experience very poor outcomes, as measured by their duration of subsequent therapy and OS. Data were generally consistent between the US and Japan. The development of new safe and effective therapies after cBTKi is needed to address the growing unmet medical need in this treatment setting.
The dense-core plaques of Alzheimer’s disease are granulomas
Authors: Greg Lemke, Youtong Huang
Journal: The Journal of Experimental Medicine (2022)

Dense-core plaques, whose centers contain highly polymerized and compacted aggregates of amyloid β peptides, are one of the two defining histopathological features of Alzheimer’s disease. Recent findings indicate that these plaques do not form spontaneously but are instead constructed by microglia, the tissue macrophages of the central nervous system. We discuss cellular, structural, functional, and gene expression criteria by which the microglial assembly of dense-core plaques in the Alzheimer’s brain parallels the construction of granulomas by macrophages in other settings. We compare the genesis of these plaques to the macrophage assembly of mycobacterial granulomas, the defining histopathological features of tuberculosis. We suggest that if dense-core plaques are indeed granulomas, their simple disassembly may be contraindicated as an Alzheimer’s therapy.